Abstract Despite wide deployment of malaria control interventions in the past decade, Sub-Saharan Africa continues to carry a disproportionate share of the global burden and of malaria-related deaths. Two key strategies for reducing the malaria burden in young children are Seasonal Malaria Chemoprevention (SMC), and pre- referral treatment, followed by immediate referral of children with severe malaria in the community to health facilities equipped for appropriate management of life-threatening malaria. However, despite significant investments in malaria control interventions by the Government of Mali and donors, the impact on burden of the disease in young children has been less than expected. Thus, the overall goal of this application is to improve the effectiveness of 1) SMC implementation and 2) Referral and management of severe disease in rural Mali and consist of two projects: a Study Type 2 (Observational studies) and Study Type 3 (Implementation studies). The specific aims of Study Type 2 are: 1) To describe the community and health systems context for implementation of SMC, and implementation of protocols for referral and management of severe malaria; 2) To explore factors determining success, and barriers and pitfalls related to the SMC implementation strategy including perception of SMC in the population and by health providers, delivery strategy and coverage, and sustainability; and 3) To evaluate household and health system responses to severe malaria, including provision of appropriate pre-referral management, and implementation of case management protocols. These aims will be addressed through quantitative and qualitative surveys and observations at community and health facilities levels. The Study Type 3 will assess the effectiveness and long-term impact of SMC on the epidemiology of malaria. The specific aims are: 1) To assess the impact of extended SMC on the incidence and prevalence of malaria among children under 5 and older children (5-10years) in intervention areas vs. control; 2) To determine the long-term effect of SMC on acquisition of immunity, parasite population structure, and drug resistance markers 3) To assess the cost ?effectiveness of SMC delivery and implementation strategies. The project will provide an essential evidence basis for improving these malaria control interventions in Mali and in West Africa.